Complications of cardiovascular disease, such as myocardial infarction, stroke, and peripheral vascular disease account for half of the deaths in the United States. A high level of low density lipoprotein (LDL) in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis. Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and in patients who are free of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.
Statin drugs are currently the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk. for cardiovascular disease. This class of drugs includes, inter alia, compactin, lovastatin, simvastatin, pravastatin and fluvastatin. The mechanism of action of statin drugs has been elucidated in some detail. They disrupt the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoA reductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, its inhibition leads to a reduction in the rate of formation of cholesterol in the liver.
[R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid is a statin drug. It is known by the trivial name fluvastatin and has the molecular formula (I):
depicted in free acid form.
Fluvastatin is commercially available under the trade name Lescol®. Fluvastatin is supplied as a monosodium salt in capsules containing the equivalent of 20 and 40 mg of fluvastatin and in extended-release tablets containing the equivalent of 80 mg of fluvastatin. Fluvastatin and its sodium salt are described in U.S. Pat. No. 4,739,073. In Example 6(a) of the '073 patent, a methyl ester precursor of (±) fluvastatin was hydrolyzed with sodium hydroxide in methanol, which yielded, after evaporation of the methanol, crude fluvastatin sodium. In Example 6(b), the fluvastatin methyl ester was hydrolyzed with sodium hydroxide in ethanol. After evaporation of the ethanol, the residue was taken up in water and lyophilized. The lyophilized product had a melting point range of 194EC-197EC. In Example 8, the sodium salt was prepared by ring opening of fluvastatin lactone with sodium hydroxide in ethanol as described in Example 6(b). The product of Example 8 produced an infrared spectrum in a KBr pellet with bands at: 3413, 2978, 2936, 1572 and 1216 cm−1.
According to U.S. Pat. No. 6,124,340, lyophilization of fluvastatin sodium as was performed in Examples 6(b) and 8 of the '073 patent yields solid fluvastatin sodium as a mixture of a crystalline form, designated as Form A, and amorphous material. The '340 patent sets forth the spectroscopic properties of another crystal form of fluvastatin sodium which is said to have low hygroscopicity and photostability. This other form is called Form B in the '340 patent. It is characterized by an infrared spectrum with bands at 3343, 2995, 1587, 1536, 1386, 1337, 1042 and 1014 cm−1 and by the following powder X-ray diffraction peak positions and intensities.
E22d (Δ)I/IO(%)4.06321.72810011.0567.9962.911.3287.8055.512.2107.24345.212.9656.82334.614.9255.9319.315.2775.7954.515.7505.62218.516.3505.41710.617.7604.99017.618.3204.83914.318.8754.69811.319.3964.5737.019.7014.50313.420.3954.35113.521.3294.1638.521.7854.07615.922.6103.9297.523.8683.7255.424.2813.6633.624.4633.6363.625.4463.4985.625.6553.4703.626.3573.3793.327.0403.2952.828.7473.1033.429.9402.9822.832.1652.7811.635.1732.5491.037.1312.4191.3
Fluvastatin sodium Form A is said to have the following powder X-ray diffraction peak positions and intensities.
E22d (Δ)I/IO (%)3.96522.2651007.93611.1310.910.5548.3751.710.6458.3041.511.9317.41244.512.2157.24014.514.4966.1061.114.8125.9760.815.9165.5640.317.7694.9883.218.6404.7565.319.8564.4685.820.5184.3252.920.9084.2451.221.3894.1511.321.7224.0881.122.6753.9180.824.0893.6911.024.5333.6260.526.5193.3580.227.9733.1870.928.8613.091
U.S. Patent Application Publication No. 2003/0032666 reports the existence of four crystal forms of fluvastatin monosodium called Forms C, D, E and F. The water content of the forms ranges between 3 and 32%. The new crystal forms of fluvastatin sodium were obtained by storing the samples under atmospheres ranging between 20 and 90% relative humidity.
According to the '666 publication, the PXRD pattern of fluvastatin sodium Form C possesses characteristic peaks at the following d-values and qualitative intensities:
d (Δ)Intensity23.8(vs)11.8(w)7.8(vs)7.6(vw)7.4(vw)6.4(vw)6.1(vw)5.90(w)5.00(vw)4.88(w)4.73(m)4.56(w)4.40(vw)4.12(vw)4.03(vw)3.96(vw)3.50(vw)3.36(vw)2.93(vw)wherein (vs)=very strong intensity; (s)=strong intensity; (m)=medium intensity; (w)=weak intensity; and (vw)=very weak intensity.
According to the '666 publication, the PXRD pattern of fluvastatin sodium Form D possesses characteristic peaks at the following d-values and qualitative intensities:
d (Δ)Intensity24.6(vs)12.5(w)8.3(vs)7.4(vw)6.2(m)4.97(w)4.85(vw)4.52(vw)4.40(vw)4.14(vw)3.96(vw)3.41(vw)3.10(vw)
According to the '666 publication, the PXRD pattern of fluvastatin sodium Form E possesses characteristic peaks at the following d-values and qualitative intensities:
d (Δ)Intensity27.6(m)13.9(vw)9.2(m)8.5(vw)8.1(vw)7.4(vw)6.9(s)6.1(vw)4.98(m)4.77(m)4.63(m)4.15(w)4.03(w)3.97(vw)3.52(vw)3.33(vw)3.08(vw)2.99(vw)
According to the '666 publication, the PXRD pattern of fluvastatin sodium Form F possesses characteristic peaks at the following d-values and qualitative intensities:
d (Δ)Intensity29.6(w)14.8(vw)9.9(w)8.6(vw)8.3(vw)7.4(s)6.6(vw)6.2(vw)5.93(w)5.03(m)4.94(m)4.35(vw)4.23(w)3.98(vw)3.54(vw)2.98(vw)
It also deserves mention that International Publication No. WO 02/36563 discloses crystal forms of enantiomerically pure [3R,5S] and [3S,5R] fluvastatin sodium.
The present invention also relates to fluvastatin sodium and the properties that it can exhibit in the condensed phase. The occurrence of different crystal forms (polymorphism) is a property of some molecules and molecular complexes. A single molecule, like the fluvastatin in formula (I) or a salt complex like fluvastatin sodium, may give rise to a variety of solids having distinct physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and NMR spectrum. The crystalline form may give rise to thermal behavior different from that of the amorphous material or another crystalline form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”) and differential scanning calorimetry (“DSC”) and can be used to distinguish some polymorphic forms from others. The differences in the physical properties of different crystalline forms result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family. These properties can be influenced by controlling the conditions under which the salt is obtained in solid form.
Exemplary solid state physical properties include the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. On the other hand, the method is not advantageous where the effectiveness of a drug correlates with peak bloodstream levels of the drug, as in the case of statin drugs. With a statin drug, provided the drug is rapidly absorbed by the GI system, a more rapidly dissolving form is likely to exhibit increased effectiveness over a comparable amount of a more slowly dissolving form.
It is often the case that the most rapidly dissolving solid state of a compound is amorphous. Amorphous forms are often less stable than crystalline forms because they do not have many of the stabilizing intermolecular interactions that are present in crystalline forms. With an amorphous form, therefore, stabilizing intermolecular interactions do not have to be broken when the compound goes into solution, and so the dissolution rate is not retarded. Although they are more rapidly dissolving than crystalline forms, amorphous forms of a compound can have disadvantages. A compound, when it is in an amorphous state, is frequently more hygroscopic than a crystalline form of the same compound (although exceptions abound, such as when the crystal has wide channels that allow water to enter and leave the crystal in response to changes in moisture density outside the crystal). Water has been implicated in drug stability problems. For instance the decomposition of aspirin which leads to the characteristic smell of vinegar when an old bottle of aspirin is opened is a hydrolysis reaction catalyzed by water. It is thus prudent when selecting a solid state form of a compound that is to be used as a drug, and possibly stored for a long time between packaging and use, to select a form that has low permeability to water. In the case of fluvastatin monosodium, a crystalline form designated Form B has already been discovered that is purportedly less hygroscopic than the partially crystalline/partially amorphous form of the salt that is obtained by following procedures in U.S. Pat. No. 4,739,073.
Although six distinct crystalline forms of racemic fluvastatin sodium have been reported to date, and at least one of them is purported to be less hygroscopic that the solid state form originally reported by the discovers of the compound, the discovery of yet other crystalline forms of fluvastatin sodium is desirable. The discovery of new crystalline forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product by enlarging the repertoire of materials that a formulation scientist has available for designing. For example, new crystalline forms can be used to design a pharmaceutical dosage form of a drug with low hygroscopicity, a targeted release profile, consistent dosing (enabled by good flow of the tableting composition into the tableting die), or other desired characteristic. New polymorphic forms and solvates of fluvastatin have now been discovered.